CN114569727B - Composition for treating cancer and application and medicine thereof - Google Patents
Composition for treating cancer and application and medicine thereof Download PDFInfo
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- CN114569727B CN114569727B CN202011383945.8A CN202011383945A CN114569727B CN 114569727 B CN114569727 B CN 114569727B CN 202011383945 A CN202011383945 A CN 202011383945A CN 114569727 B CN114569727 B CN 114569727B
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Classifications
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
- A61K39/3955—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against proteinaceous materials, e.g. enzymes, hormones, lymphokines
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Abstract
The invention relates to the technical field of medicines, and particularly discloses a composition for treating cancers, application thereof and a medicine. The compositions of the invention include an SGLT1 inhibitor and a HER2 inhibitor. The invention discovers that SGLT1 has interaction with HER2 and promotes the occurrence and development of tumors; meanwhile, the HER 2-targeted inhibitor and SGLT1 inhibitor composition has a synergistic anti-tumor effect, and the HER 2-and SGLT 1-targeted inhibitor composition can be used for cancer treatment and preparation of anti-cancer drugs.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a composition for treating cancers, and application and medicines thereof.
Background
As early as the 80 s of the 19 th century, scientists have found that HER2 protein has the ability to convert normal fibroblasts into cancer cells and defined HER2 as a proto-oncogene (Shih C, padhy LC, murray M, weinberg RA.transformation genes of carcinomas and neuroblastomas introduced into mouse fibrilasts. Nature 1981; 290:261-264.). A large number of clinical experimental data have thereafter shown that gene amplification and protein overexpression of HER2 is present in about 25-30% of breast and ovarian cancers. For example, breast cancer can have up to 25-50 copies of the HER2 gene and 40-100 fold increases in HER2 protein ultimately form 200 tens of thousands of HER2 receptors on the surface of tumor cells, much higher than normal ductal epithelial cells of the breast (Venter DJ, tuzi NL, kumar S, gullick wj. Overhexpress of the c-erbB-2oncoprotein in human breast carcinomas:immunohistological assessment correlates with gene amplification.Lancet 1987;2:69-72). In addition to the up-regulation of HER2 protein expression caused by gene amplification, studies have recently found that constitutively active mutations in HER2 enzyme activity also occur in various cancers. High mutation rate (> 10%) carcinoma species include prostate neuroendocrine carcinoma, metastatic skin squamous cell carcinoma, and bladder urothelial carcinoma. Furthermore, HER2 mutations also occur in common cancers such as lung, colorectal and breast cancers (Connell CM, doherty GJ. Activating HER2 mutations as emerging targets in multiple solid markers. ESMO open.2017; 2[5]: e 000279.) and gene amplification of HER2 and constitutive enzyme activity mutations are often associated with poor prognosis of tumors. Subsequent extensive studies have shown that expansion of HER2 and active mutations are dependent on tumor cell growth, knocking down HER2 inhibits tumor cell growth and causes tumor cell death (Faltus T, yuan J, zimmer B, kramer A, loibl S, kaufmann et al Silencing of the HER/neu gene by siRNA inhibits proliferation and induces apoptosis in HER2/neuoverexpressing breast cancer cells.Neoplasia 2004; 6:786-795.). These studies above indicate that HER2 is a good target for tumor therapy. Thus, monoclonal antibody HER2 inhibitors represented by trastuzumab, and recently developed small molecule inhibitors such as lapatinib, lenatinib, tu Kati, and antibody-coupled drugs based on trastuzumab have been developed around the HER2 target. The use of these drugs alone in combination with classical chemotherapeutics significantly improved the outcome of treatment of HER2 positive cancers (Baselga J, cortes J, kim SB, im SA, hegg R, im YH, et al Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer N Engl J Med.2012;366[ 2:109-19 ]. However, consistent with the problems of other targeting drugs in treating cancer, HER2 mab and TKI drugs generally have drug resistance, and how to overcome the drug resistance to enhance the killing property of the targeting drug is a urgent problem to be solved.
One of the markers of tumor cells that differs from normal cells is that cancer cells preferentially use aerobic glycolysis to energize tumor cells even under oxygen-rich conditions. Aerobic glycolysis is much less energy efficient than oxidative phosphorylation, requiring a significant increase in the glucose transport capacity of tumor cells (Hanahan D et al Hallmarks of cancer: the next generation, cell,144 (5): 646-674 (2011), which is achieved by overexpression of plasma membrane transporters (Ganapathy V, et al Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond, pharmacology)&Therapeutical 121 (1): 29-40 (2009). Glucose cotransporter 1 (SGLT 1) is an active glucose transporter that relies on extracellular sodium concentration to transport glucose to cells independent of glucose concentration (Wright EM, et al Biology of human sodium glucose transporters, physiological Reviews,91 (2): 733-794 (2011)). Studies have shown that SGLT1 is highly expressed in a variety of cancers and is associated with poor prognosis of cancers including breast cancer, ovarian cancer, oral squamous cell carcinoma, colorectal cancer, pancreatic cancer, and prostate cancer. SGLT1 can bind and stabilize EGFR so as to promote the growth and proliferation of tumor cells, and gefitinib resistant cell lines can be sensitized to gefitinib again by combining phlorizin serving as a phlorizin SGLT1 inhibitor with gefitinib serving as an EGFR inhibitorJ,Vrhovac/>I,Gajski G,/>J,GarajVrhovac V.Apigenin:A dietary flavonoid with diverse anticancer properties.Cancer Lett 2018；413:11-22.Koepsell H.The Na+ -D-glucose cotransporters SGLT1 and SGLT2 are targets for the treatment of diabetes and cancer.Pharmacol Ther 2017；170:148–65.Yamazaki Y,Harada S, Tokuyama S.Sodium–glucose transporteras a novel therapeutic target in treatment Eur J of Pharmacol 2018; 822:25-31). SGLT1 inhibitors thus have the ability to reverse EGFR inhibitor resistance to interact with them.
At present, no report of combining an SGLT1 inhibitor with a small molecule inhibitor and a monoclonal antibody drug for solving the problem of treating cancers resistant to HER2 tyrosine kinase inhibitors in the field is known.
Disclosure of Invention
Accordingly, it is an object of the present invention to provide a composition for treating cancer such that the HER2 inhibitor and SGLT1 inhibitor in the composition have synergistic anti-tumor effects;
it is another object of the present invention to provide the use of the above composition in the preparation of a medicament for treating cancer;
it is another object of the present invention to provide a medicament for treating cancer comprising the above composition;
in order to achieve the above purpose, the present invention provides the following technical solutions:
a composition for treating cancer comprising an SGLT1 inhibitor and a HER2 inhibitor.
The invention discovers that SGLT1 and HER2 have interaction and promote the occurrence and development of tumors, the interaction plays an important role in the function of each other, the knocking down of HER2 can influence the proliferation and the transfer of growth signals of tumor cells and also influence the function of SGLT1, otherwise, the knocking down of SGLT1 can influence the survival of cancer cells under the condition of low sugar and also influence the proliferation of HER2 signal paths and cells, so that the combined use of inhibitors of the two can be expected to produce a synergistic anti-tumor effect; experiments prove that the composition consisting of the HER2 inhibitor and the SGLT1 inhibitor has a remarkable inhibition effect on tumor growth, and the composition has a remarkable synergistic effect on tumor inhibition.
Accordingly, the present invention provides the use of the above composition in the preparation of a medicament for the treatment of cancer; such cancers include, but are not limited to, bladder cancer, blood cancer, bone cancer, brain cancer, breast cancer, central nervous system cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, gallbladder cancer, gastrointestinal cancer, external genital cancer, genitourinary tract cancer, head cancer, kidney cancer, laryngeal cancer, liver cancer, lung cancer, cancer of muscle tissue, neck cancer, oral or nasal mucosa cancer, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, spleen cancer, small intestine cancer, large intestine cancer, stomach cancer, testicular cancer, and thyroid cancer.
Preferably, the concentration of 0 < SGLT1 inhibitor in the composition is less than or equal to 100. Mu.M, and the concentration of 0 < HER2 inhibitor in the composition is less than or equal to 100. Mu.M. In specific embodiments of the invention, the SGLT1 inhibitor concentration is 5, 10, 20, 30, 40 or 60 μm and the HER2 inhibitor concentration is 0.1, 2.5, 5, 10, 20, 40, 50, 60, 80 or 100 μm.
In a specific embodiment of the present invention, the SGLT1 inhibitor is selected from one or more of the group consisting of soligliflozin, SY-009 (purchased from the treasures pharmaceutical industry), and Licogliflozin (purchased from the nohua pharmaceutical industry); the HER2 inhibitor is selected from one or more than two of lapatinib, lenatinib, saprolitinib, wave Ji Tini, fig. calitinib, lapatinib xylene sulfonate and HER 2-targeted monoclonal antibodies. Wherein, the HER2 targeting mab such as trastuzumab is not limited thereto, and those skilled in the art consider that feasible HER2 targeting mab is within the scope of the present invention.
According to the application provided by the invention, the invention also provides a medicament for treating cancer, which comprises the composition and pharmaceutically acceptable auxiliary agents.
Preferably, the pharmaceutical dosage form is a variety of dosage forms of oral medicaments, including but not limited to, granule, pill, powder, tablet, capsule, oral liquid, syrup, and the like.
According to the technical scheme, the invention discovers that SGLT1 and HER2 have interaction and promote the occurrence and development of tumors; meanwhile, the HER 2-targeted inhibitor and SGLT1 inhibitor composition has a synergistic anti-tumor effect, and the HER 2-and SGLT 1-targeted inhibitor composition can be used for cancer treatment and preparation of anti-cancer drugs.
Drawings
FIG. 1 shows the results of HER2 (i.e., ERBB2 in the figure) and SGLT1 high expression associated with poor prognosis in breast cancer patients; wherein 1A is the relationship between HER2 high expression and prognosis of breast cancer patients, 1B is the relationship between HER2 high expression and prognosis of ovarian cancer patients, 1C is the relationship between SGLT1 high expression and prognosis of breast cancer patients, and 1D is the relationship between SGLT1 high expression and prognosis of ovarian cancer patients;
the HER2 (ERBB 2 in the figure) and SGLT1 (SLC 5A1 in the figure) and SGLT2 (SLC 5A2 in the figure) shown in fig. 2 have positive correlation in breast cancer and ovarian cancer to obtain results; wherein 2A is positive correlation between HER2 and SGLT1 expression in breast cancer, and 2B is positive correlation between HER2 and SGLT1 expression in ovarian cancer; 2C is positive correlation of HER2 with SGLT2 expression in breast cancer, and 2D is positive correlation of HER2 with SGLT2 expression in ovarian cancer;
FIG. 3 shows the effect on HER2 protein levels after knockout/overexpression of SGLT1 in ovarian cancer cell lines; the level of HER2 protein decreases with the knocking out SGLT1, and the level of HER2 protein increases with the overexpression of SGLT 1; 3A is the level of HER2 protein detected after SGLT1 and SGLT2 are knocked out, 3B is the detection of SGLT1 knockdown effect, and 3C is the increase in HER2 protein level by over-expression of SGLT 1; wherein C is a normal control group, S1 is knockdown SGLT1, S2 is knockdown SGLT2, H1 and H2 are knockdown HER2, MG132 is a positive control;
FIG. 4 shows the effect of SGLT1 on HER2 protein stability; 4A is the stability of the SGLT 1-knocked down HER2 protein, and 4B is the increased stability of HER2 protein after SGLT1 overexpression; wherein the assay shows the stability of HER2 protein with varying levels of HER2 protein in cells treated with the protein synthesis inhibitor cycloheximide for different durations (0, 2, 4, 8 h);
figure 5 shows the effect of HER2 knockdown on glucose uptake by cells; wherein, C represents a normal control group, H1 represents a knock-down HER2 group;
figure 6 shows the effect of HER2 and SGLT1 inhibitors alone and in combination on HER2 signaling pathway; wherein, C is normal control, T is the abbreviation of HER2 inhibitor, namely, the graphic cartinib, S is the abbreviation of SGLT1 inhibitor, namely, the Sogliflozin, and TS is the combination of the two inhibitors;
immunoblotting test results of HER2 and SGLT1 shown in fig. 7;
the effect of HER2 inhibitor, fig. 8-14, on various cancer cell lines, fig. calitinib and SGLT1 inhibitor, sogliflozin; FIG. 8 shows that HER2 inhibitors and SGLT1 inhibitors treat gastric cancer cell line HGC27; FIG. 9 shows that HER2 inhibitors and SGLT1 inhibitors treat cervical cancer cell line HeLa; FIG. 10 shows treatment of breast cancer cell line MCF-7 with HER2 inhibitor and SGLT1 inhibitor; FIG. 11 shows that HER2 inhibitor and SGLT1 inhibitor treat liver cancer cell line QGY-7703; figure 12 shows that HER2 inhibitor and SGLT1 inhibitor treat prostate cancer cell line DU145; FIG. 13 shows treatment of a node esophageal cancer cell line KYSE30 with a HER2 inhibitor and an SGLT1 inhibitor; figure 14 shows that HER2 inhibitors and SGLT1 inhibitors treat cholangiocarcinoma cell line RBE; wherein S represents the Sogliflozin, and the numerical values listed after the equal sign in each graph are the concentration mu M of the Sogliflozin;
figures 15-16 show the effect of HER2 inhibitor, critinib, and various SGLT1 inhibitors on tumor colorectal cancer cell line SW 620; wherein S represents Sogliflozin, target3 represents Licogliflozin (Norhua pharmaceutical), target5 represents SY-009 (Yabao pharmaceutical industry), and the values after the figures are equal numbers corresponding to the concentration mu M of the SGLT1 inhibitor;
FIG. 17 shows the results of the treatment of a high HER2 expressing ovarian cancer cell line SKOV3 with the various HER2 inhibitors and the SGLT1 inhibitor, sogliflozin; 10-1 to 10-5 show the tumor inhibiting effect of lapatinib (10-1), lenatinib (10-2), saprolidine (10-3), wave Ji Tini (10-4), lapatinib xylene sulfonate (10-5) in combination with the SGLT1 inhibitor, sogliflozin; wherein S represents the concentration μM of the same number as listed in each figure, and the column with concentration 0 represents the concentration of both the HER2 inhibitor and SGLT1 inhibitor, namely, the concentration of the same.
Detailed Description
The invention discloses a composition for treating cancers, application and medicaments thereof, and a person skilled in the art can appropriately improve the technological parameters by referring to the content of the invention. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included in the present invention. While the compositions and uses and medicaments of the present invention have been described in terms of preferred embodiments, it will be apparent to those skilled in the relevant art that the compositions and uses and medicaments of the invention can be modified or adapted and combined to implement and use the present technology without departing from the spirit, scope and scope of the invention.
The present invention analyzed by TCGA data that poor prognosis of malignancy is associated with overexpression of epidermal growth factor receptor 2 (HER 2) and sodium/glucose cotransporter 1 (SGLT 1). The cancer includes breast cancer, ovarian cancer and other cancers.
The invention discovers that SGLT1 and HER2 have interaction, and the interaction plays an important role in the function of each other, so that knocking down HER2 can influence proliferation and transfer of growth signals of tumor cells and also influence SGLT1 functions, otherwise, knocking down SGLT1 can influence survival of cancer cells under low-sugar conditions and influence the channel of HER2 signals and proliferation of cells. Therefore, the composition consisting of the HER2 inhibitor and the SGLT1 inhibitor has a remarkable inhibition effect on tumor growth, and has a remarkable synergistic effect on tumor inhibition.
In a specific embodiment of the invention, the following experimental verification was performed:
(1) Effect of high expression of HER2, SGLT1, SGLT2 in ovarian and breast cancer on poor prognosis of cancer patients;
(2) SGLT1 effect on HER2 signaling pathway;
(3) HER2 functions normally on SGLT1 function;
(4) Interactions between HER2 and SGLT 1;
(5) Effect of HER2 and SGLT1 inhibitors alone and in combination on tumor cells;
the experimental procedures and methods involved in the above experiments can be referred to as follows:
1. cells and reagents
The liver cancer cell line QGY7703 used in the invention; colorectal cancer cell lines SW620, HCT116, SW480, LOVO, HT29, DLD1; cervical cancer HeLa; ovarian cancer SKOV3; gastric cancer NGC27; bile duct cancer RBE; esophageal carcinoma KYSE30 and HEK293T cell lines were both cultured from the American Type Culture Collection (ATCC) in 37℃incubator containing 5% CO2 in DMEM or RPMI 1640 (Gibico) supplemented with 10% fetal bovine serum (Gibico) and 1% penicillin/streptomycin. Mouse anti-Flag tag antibody (F3165), flag antibody European M2 microbeads were purchased from Sigma-Aldrich (St. Louis, MO), rabbit GAPDH reference antibody, horseradish peroxidase-labeled anti-rabbit and mouse secondary antibodies were purchased from Boolong corporation. Sotagliflozin, apatinib and lenvatinib are all available from Selleckchem (Houston, TX). Antibodies against pERK (4370) were obtained from Cell Signaling (Danvers, MA). The MTT kit (catalog number 30-1010K) was obtained from ATCC.
2. Plasmid construction
Human wild type HER2 was cloned into pCMV-tag2B vector and human wild type SGLT1 sequence was cloned into pEGFP-N1 vector. Targeting the Sglt1-1 shRNA sequence 5'-AGGAGAGCCTATGACCTATTT-3'; 5'-GCCTGATG CTATCAGTCATGC-3' Sglt1-2 shRNA sequence; 5'-GCATATTTCCTGC TGGTCATT-3' Sglt2-1 shRNA sequence; 5'-GGTCATCACGATGCCACAGTA-3' Sglt2-2 shRNA sequence; 5'-GATGAAAGTTACCAGTCTATT-3' for HER2-1 shRNA sequence; HER2-2 shRNA sequence 5'-GCTGACATGTACGGTCTATGC-3' sequence shRNA was constructed into pLVX-shRNA2-puro vectors for subsequent lentivirus coating to construct SGLT1, SGLT2, HER2 knockdown cell lines. All vectors were verified by sequencing to be correct plasmids.
3. Transient transfection and co-immunoprecipitation
HEK293T cells were transfected with Flag-tagged SGLT1 expressing plasmid alone or mixed with designated GFP-tagged HER2 vector in serum-free DMEM medium and added with the transfection reagent PEI. After 6 hours of transfection the medium was replaced with 10% serum, 24 hours after medium replacement, the medium was discarded, the cells were blown up with 10 ml of 1 XPhosphate buffer washing (PBS) and centrifuged at 1500 revolutions, the pellet of the cell mass obtained by discarding the supernatant was added to RIPA buffer (50 mM Tris-HCl, pH 8.0, with 150mM sodium chloride, 1.0% Igepal CA-630 (NP-40), 0.5% sodium deoxycholate and 0.1% sodium dodecyl sulfate) supplemented with a protease inhibitor mixture and lysed at 4℃for 30 minutes on a shaker. Then, the cell lysate was centrifuged at 12000X rpm for 10 minutes. The supernatant was added to M2 microbeads conjugated with Flag antibodies and incubated overnight at 4 ℃. The samples were then centrifuged, washed three times with RIPA buffer, boiled in Laemmle buffer (Biorad, CA) and analysed by western blotting with 8% sds PAGE gel.
4. Western blot analysis
For Western blot analysis, cells were lysed with the appropriate volume of RIPA buffer (150mM NaCl,50mM Tris-HCl, pH 7.4,0.1% sds,1% triton x-100,1mM EDTA,1mM PMSF,1% sodium deoxycholate, 1mM NaF,1mM Na3VO4 in deionized water) at 4 ℃ or on ice for more than 30 minutes. Centrifugation was carried out at 12000X rpm for 10 minutes, and the supernatant was subjected to protein concentration measurement using BCA kit (Thermo) and then to 5X loading Buffer and boiled at 100℃for 10 minutes. After brief centrifugation, samples were transferred to PVDF membranes after electrophoretic separation by 10% sds-PAGE, followed by blocking with 5% nonfat milk powder for more than one hour, and then incubated overnight at 4 ℃ with primary antibody at optimal concentration. Membranes were washed 3 times with 0.1% pbst (1×tbs,0.1% tween-20) for 10 minutes each, then incubated with secondary antibody for 1 hour at room temperature. The signal is visualized by enhancing chemiluminescence.
5. Cell growth assay
According to the protocol provided by the manufacturer, the detection principle is that succinate dehydrogenase in mitochondria of living cells can reduce exogenous MTT into water-insoluble blue-violet crystalline Formazan (Formazan) and deposit in cells, while dead cells have no function. Dimethyl sulfoxide (DMSO) can dissolve formazan in cells, and the light absorption value of the formazan can be measured at 570nm wavelength by an enzyme-linked immunosorbent assay, so that the number of living cells can be indirectly reflected. Cell growth was determined by 3- (4, 5-dimethylthiazol-2-yl) -2, 5-diphenyltetrazolium bromide (MTT) assay in 96 well plates. Specifically, cells were resuspended in a system of 5000 cells per 200 μl of medium and plated in each well of a 96-well plate. The next day, the medium was replaced with medium containing different concentrations of sogliflozin, HER2 inhibitor, and combinations therebetween. After 48 or 72 hours incubation with the drug, 20 μl of MTT reagent was added to each well and incubated for 2 hours. After the media is discarded, the formazan pellet in the cells is dissolved in 100 μl DMSO. Absorbance was measured at 570nm by an enzyme-labeled instrument. Quadruplicate samples were used in each group.
7. Statistical analysis
Student's t-test was used to evaluate the difference in growth of cells and nude mice transplanted tumor growth under different combination conditions at different concentrations of SGLT1 and HER2 inhibitors such as sogliflozin, apatinib, lenvatinib, etc. P values less than 0.05 were defined as statistically significant.
The composition for treating cancer, the application thereof and reagents or instruments used in the medicaments can be purchased from the market; the comparison experiments were performed with the exception of the differences that were due, and other experimental conditions were kept consistent for comparison, unless specifically indicated otherwise.
The invention is further illustrated by the following examples.
Example 1: HER2 and SGLT1 high expression are positively correlated and correlated with poor prognosis for cancer patients
In fig. 1, 1A and 1B analyze the correlation between HER2 expression levels in ovarian cancer and breast cancer patient cancer tissues and the total survival of the patients through the TCGA database to obtain that the total survival of the patients with high HER2 expression is shorter; 1C,1D analyzes the relevance between SGLT1 expression level in cancer tissues of ovarian cancer and breast cancer patients and the total survival time of the patients through a TCGA database to obtain that the total survival time of the patients with high SGLT1 expression is shorter; it was demonstrated that high expression of HER2 and SGLT1 was associated with poor prognosis in both cancer patients, indicating a relationship between both in tumor cell expression itself and prognosis.
In this example, survival analysis of HER2 and SGLT1 and SGLT2 expression levels and total survival time of ovarian cancer and colorectal cancer patients was performed by mining TCGA database, and it was found that high HER2 and SGLT1 expression levels were positively correlated with poor prognosis of ovarian cancer and breast cancer patients.
This example demonstrates by way of example only that high expression of HER2 and SGLT1 correlates with poor prognosis in both cancer patients, demonstrating the relationship of both to prognosis in the expression of tumor cells themselves. This is not to be limited to compositions of embodiments of the invention being limited to ovarian and colorectal cancers. In other embodiments of the present invention, the composition has a remarkable inhibitory effect on various cancers such as cervical cancer, prostate cancer, liver cancer, colorectal cancer, gastric cancer, esophageal cancer, cholangiocarcinoma cell lines and the like, as shown in fig. 8 and 9.
In addition, the present invention also found that there was a positive correlation between HER2 and SGLT1 expression and no correlation with SGLT2 expression by pearson's test on HER2 and SGLT1, SGLT2 expression amount data in ovarian cancer and breast cancer patients obtained from TCGA database, as shown in fig. 2A, 2B, 2C, 2D. This suggests that HER2 has a certain correlation with SGLT1 functions.
Example 2: functional interactions of HER2 and SGLT1 on each other
After knocking down SGLT1, SGLT2 and HER2 from ovarian cancer cell line SKOV3 using shRNA technology and after over-expressing SGLT1 using exogenous vectors, the Western test results of fig. 3 show that 3a,3c demonstrate that the protein level of SGLT1 knocked down, HER2 is reduced and the protein level of over-expressed SGLT1, HER2 is increased; however, the protein level of HER2 was unchanged by knocking down SGLT 2. It is shown that SGLT1 affects the function of HER2 protein, but SGLT2 does not affect the function of HER2 protein;
in addition, whether knockdown or over-expression of SGLT1 would correspondingly shorten or lengthen HER2 half-life was assessed by observing protein half-life using the protein translation inhibitor cycloheximide to inhibit protein translation. After SGLT1 is knocked down from an ovarian cancer cell line SKOV3 by using shRNA technology and SGLT1 is overexpressed by using an exogenous vector, the change of HER2 protein level with time is observed after cycloheximide serving as a protein translation inhibitor is added to a cell culture solution, and as a result, as shown in fig. 4A and 4B, the half-life of HER2 after SGLT1 is knocked down is remarkably shortened, and the half-life of HER2 after SGLT1 is overexpressed is remarkably prolonged. The SGLT1 is critical to the stability of HER2 protein, and the degradation of HER2 can be realized by targeting the SGLT1
The above results demonstrate that SGLT1 affects the protein stability of HER 2. To further determine the effect of HER 2on SGLT1, the ratio of FITC positive cells was detected by flow cytometry after knocking down HER2 from ovarian cancer cell line SKOV3 by shRNA technique and after treating the cells for 30 min with FITC fluorescence conjugated glucose analog 2-BNDG, and the statistical summary results are shown in fig. 5, in which the uptake capacity of 2-NBDG by the cells after knocking out HER2 is significantly reduced, i.e. knocking out HER2 affects the uptake of glucose by the cells. These results indicate that HER2 in turn also has an effect on the function of SGLT1, which are mutually influencing.
It is worth mentioning that the invention only takes ovarian cancer SKOV3 cells as an example to knock down the genes to evaluate the mutual influence between the genes, and the conclusion of the invention should not be limited to the cancer species and cell lines.
Example 3: SGLT1 effect on HER2 signaling pathway
SKOV3 cells were treated with HER2 and SGLT1 inhibitors, either alone or in combination, to detect HER2 and HER2 downstream molecule p-ERK1/2. The results of fig. 6 show that HER2 and SGLT1 inhibitors in combination better inhibited HER2 signaling pathway activation, demonstrating that the effect of the combination is superior to either target inhibitor alone.
Example 4: intermolecular interactions between HER2 and SGLT1
This example further determines the intermolecular interactions of HER2 with SGLT1 by co-immunoprecipitation experiments. The method of co-immunoprecipitation was used to co-transfect 293T cells with FLAG-tagged SGLT1 and HA-tagged HER2 vector, lyse the cells after 24 hours, add FLAG beads and bind for 5 hours, and perform Western detection using HA antibody and FLAG antibody, the specific method is as follows:
HEK293T cells were transfected with Flag-tagged SGLT1 expressing plasmid alone or mixed with designated HA-tagged HER2 vector in serum-free DMEM medium and added with transfection reagent PEI. After 6 hours of transfection the medium was replaced with 10% serum, 24 hours after medium replacement, the medium was discarded, the cells were blown up with 10 ml of 1 XPhosphate buffer washing (PBS) and centrifuged at 1500 revolutions, the pellet of the cell mass obtained by discarding the supernatant was added to RIPA buffer (50 mM Tris-HCl, pH 8.0, with 150mM sodium chloride, 1.0% Igepal CA-630 (NP-40), 0.5% sodium deoxycholate and 0.1% sodium dodecyl sulfate) supplemented with a protease inhibitor mixture and lysed at 4℃for 30 minutes on a shaker. Then, the cell lysate was centrifuged at 12000X rpm for 10 minutes. The supernatant was added to M2 microbeads conjugated with Flag antibodies and incubated overnight at 4 ℃. The samples were then centrifuged, washed three times with RIPA buffer, boiled in Laemmle buffer (Biorad, CA) and analysed by western blotting with 8% sds PAGE gel. IP = immunoprecipitation, and Input = expression level of the foreign protein specified in HEK293 whole cell lysates used for immunoprecipitation. The results are shown in figure 7, where there is a protein interaction between HER2 and SGLT 1.
Example 5: inhibition of SGLT1 by SGLT1 inhibitors to sensitize cancer cells to HER2 inhibitors
Figures 8-14 illustrate by way of example only the IC50 values for evaluating the HER2 inhibitor, icotinib, and the SGLT1 inhibitor, soliglibenclamide, alone and in combination with HER2 inhibitor, icotinib, in hepatoma cell line QGY-7703, prostate cancer cell line DU145, and other 5 common cancer cell lines. The results show that the combination of the SGLT1 inhibitor, namely the sogliflozin, and the HER2 inhibitor, namely the flecaitinib, can obviously reduce the IC50 value of the flecaitinib and increase the sensitivity of the flecaitinib to cancer cells, and show that the combination of the two has a synergistic effect;
meanwhile, colorectal cancer cell line SW620 was treated with HER2 inhibitor, critinib, and a different SGLT1 inhibitor, and IC50 values of HER2 inhibitor, critinib, were measured using the MTT method, separately for HER2 inhibitor and SGLT1 inhibitor single drug, and for the combination of the two different dose compositions. The results in figures 15-16 show that other SGLT1 inhibitor compositions than soligliflozin also have synergistic effects on colorectal cancer cell lines and that the effect of soligliflozin is better than SY-009 (sub-bao pharmaceutical industry) than licogliffozin (nova pharmaceutical) than phlorizin (as a control).
In addition, treatment of ovarian cancer cell line SKOV3, which highly expresses HER2, with a plurality of HER2 inhibitors and SGLT1 inhibitors examined the inhibitory effect of a combination of both a plurality of HER2 inhibitors and the preferred SGLT1 inhibitor, soligliflozin, on tumor growth. The results of fig. 17 demonstrate that gliflozin works well in combination with a variety of HER2 inhibitors, the composition has a significant inhibitory effect on tumor growth, and the HER2 inhibitor is not limited to critinib.
The foregoing is merely a preferred embodiment of the present invention and it should be noted that modifications and adaptations to those skilled in the art may be made without departing from the principles of the present invention, which are intended to be comprehended within the scope of the present invention.
Claims (4)
1. A composition for treating cancer, comprising sogliflozin and critinib; wherein:
the concentration of the Sogliflozin is 10 mu M, 20 mu M or 30 mu M;
the concentration of the critinib is less than or equal to 0.1 mu M and less than or equal to 80 mu M.
2. Use of the composition of claim 1 for the preparation of a medicament for the treatment of cancer;
the cancer is gastric cancer, cervical cancer, breast cancer, liver cancer, prostatic cancer, esophageal cancer, colon cancer or bile duct cancer.
3. A medicament for treating cancer comprising the composition of claim 1 and a pharmaceutically acceptable adjuvant.
4. A medicament according to claim 3, characterized in that it is an oral medicament.
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| CN105358173A (en) * | 2013-05-08 | 2016-02-24 | 休斯敦系统大学 | Targeting the EGFR-SGLT1 Interaction for Cancer Therapy |
| CN111601613A (en) * | 2017-12-22 | 2020-08-28 | 诺华股份有限公司 | Methods of treating metabolic disorders with FGF21 variants |
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| CN105358173A (en) * | 2013-05-08 | 2016-02-24 | 休斯敦系统大学 | Targeting the EGFR-SGLT1 Interaction for Cancer Therapy |
| CN111601613A (en) * | 2017-12-22 | 2020-08-28 | 诺华股份有限公司 | Methods of treating metabolic disorders with FGF21 variants |
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| SGLT1 is required for the survival of triple-negative breast cancer cells via potentiation of EGFR activity:Web of Science;Huiquan Liu等;Molecular Oncology;第13卷(第9期);1874-1886 * |
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